This invention relates to substituted cholesterol derivatives and, more particularly, to unilamellar and multilamellar vesicles as encapsulants for polar compounds, particularly, therapeutical agents.
Encapsulation is utilized to isolate sensitive materials from chemically aggressive environments and/or to control release of the encapsulated material at a particular time at a specified rate or at a specified site of delivery. Encapsulation can be utilized to dispense household products such as insecticides, cosmetic products such as topical products, chemical warfare agents and pharmaceuticals. Any material compatible with the encapsulant can be processed into an encapsulated form.
The microencapsulation of drugs holds great potential for increasing the efficacy of pharmaceutical therapies while reducing unwanted systemic effects by targeting specific organs for drug release. Numerous studies have employed phospholipids, both as model membranes and as carriers for a variety of biologically active materials. For example, enzymes, chelating agents, viral nucleic acids, anti-tumor drugs, antifiotics, immunogens and hormones have all been successfully encapsulated with liposome systems. Phospholipid-containing systems are inherently attractive for encapsulation since they contain lipids analogous to those found in cell membrane and thus are stabilized by the same forces that maintain cell integrity in vivo. However, these lipids are also susceptible to enzymatic degradation and may display antigenic surfaces, which can give rise to a subsequent immunological response. A major obstacle to the use of circulating liposome carriers has been their rapid uptake and removal by the liver.
The development of artificial materials for encapsulation offers an alternative approach to resolving problems of liposome instability, while increasing the versatility of these systems. Although most liposome studies have been conducted with diacyl phosphatidylcholine bilayers, a number of investigators have reported liposome formation using other amphiphiles, such as dihexadecylphosphate. Non-bilayer forming lipids, such as cholesterol or phosphatidylethanolamine have been found to form closed vesicles upon the addition of other compounds such as ceramides and fatty acids, nonionic detergents, bile acids and lysophosphatidylcholine. Bilayered structures have also been formed by single lipid molecules, containing two polar groups connected by an alkyl moiety.
Several approaches have been taken to deliver selectively liposome encapsulated materials to specific organs or types of tissues. Modification of lipid acyl groups to alter the liposome phase transition temperature can induce the preferential release of encapsulated materials at sites of inflammation and infection where the pH is slightly below the physiological level.
Alternatively, one can change the surface properties of liposomes so that they will interact specifically with cell surface groups on the targeted tissue. Successful demonstrations of this approach include the attachment of tumor cell specific antibodies to a vesicle surface and incorporation of lipid containing charged groups or carbohydrates which alter the liposome surface and tissue distribution.
These artificial materials were based on the use of fluid, acyl chains and were mainly based on phospholipid containing systems. Encapsulation was accomplished by extensive sonication to form multilayer vesicles. Sonication results in heating the vesicles which results in deactivation of thermally sensitive materials.